crizotinib and Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare and deadly malignancy with an extremely poor prognosis. The median overall survival (OS) of this disease is 12-18 months. However, the oncogenic driver mutations of MPM are rarely understood, and the targeted therapy for it is still under investigation. In this report, we describe a case of MPM with CD74-ROS1 fusion who obtains complete and durable response after receiving crizotinib. By the time of submission, the progression-free survival (PFS) with crizotinib has been 6.0 years, and the patient has survived for 7.6 years. Currently, he is still in complete remission (CR). To the best of our knowledge, this case represents the first report of CD74-ROS1 fusion identified in MPM. Meanwhile, it is also the first report of complete and long-term response to crizotinib in a patient with MPM positive for CD74-ROS1 fusion. This case report might contribute to the tumorigenesis and targeted therapy of this deadly disease.

Topics: Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Protein-Tyrosine Kinases; Proto-Oncogene Proteins

Topics: Adolescent; Antineoplastic Agents; Cisplatin; Crizotinib; Female; Humans; Lung; Lung Neoplasms; Mesothelioma; Pemetrexed; Precision Medicine

Topics: Crizotinib; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crizotinib; Drug Synergism; Female; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Nude; Microtubules; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Pleural Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Signal Transduction; Xenograft Model Antitumor Assays